In order to effectively exhibit the efficacy of a pharmaceutical product, it is required to cause a pharmacologically active compound to effect at an appropriate site in the body at an appropriate concentration for an appropriate length of time. Particularly, a cytotoxic antitumor agent is such that when systematically administered by intravenous administration or the like, the cytotoxic antitumor agent is widely distributed over the whole body and exhibits cell proliferation inhibitory action. In this case, it is reported that since cells are subjected to the pharmacologically active action without distinction between cancer cells and normal cells, serious side effects are brought about by the effect on normal cells. Therefore, in order to reduce side effects, a technology of transporting the antitumor agent to a tumor lesion is important. Thus, there is a demand for a method for controlling the pharmacokinetics in order to selectively transport an antitumor agent to a tumor tissue and to cause the antitumor agent to act at an appropriate drug concentration for an appropriate drug sensitization time.
As a method for controlling the pharmacokinetics, a method of utilizing the pharmacokinetic characteristics based on the molecular weight is known. That is, when a biocompatible polymer material is intravascularly administered, renal excretion is suppressed, and a long half-life in blood is maintained. Furthermore, since tumor tissues have high tissue permeability of polymer materials, and since recovery mechanism of polymer materials is not sufficiently constructed, it is known that polymer materials are distributed and concentrated in tumor tissues at relatively high concentrations. Thus, development of polymerized antitumor agents in which a biocompatible polymer material is used as a polymer carrier and an antitumor agent is bonded to this polymer carrier, has been implemented.
As the polymerized antitumor agents, polymerized antitumor agents have been reported, in which a block copolymer obtained by linking a polyethylene glycol segment and a polyglutamic acid segment is used as a polymer carrier, and various antitumor agents are bonded to side-chain carboxylic acids of the polyglutamic acid segment. Patent Literature 1 discloses a pharmaceutical product in which 7-ethyl-10-hydroxycamptothecin is bonded to the relevant block copolymer. Furthermore, as other antitumor agents, a block copolymer conjugate of a cytidine-based antitumor agent (Patent Literature 2), a block copolymer conjugate of combretastatin A-4 (Patent Literature 3), a block copolymer conjugate of a HSP90 inhibitor (Patent Literature 4), and the like are known. It is described that these polymerized antitumor agents have enhanced antitumor effects, compared to those low molecular weight antitumor compounds used as active ingredients.
These block copolymer conjugates of antitumor agents are polymerized antitumor agents in which hydroxyl groups of the antitumor agent are bonded to side chain carboxylic acids of the block copolymer through ester bonds to form conjugates. These are prodrugs that exhibit antitumor activity when administered into the body, by cleaving the ester bonds at a constant rate to release the antitumor agent.
Furthermore, these block copolymers having antitumor agents bonded thereto have a physical property by which, when the block region to which the antitumor agent is bonded is hydrophobic, the antitumor agent-bonded region in an aqueous solution exhibits associative properties based on a hydrophobic interaction, and multiple molecules of the block copolymer form associative aggregates.
Associative aggregates formed by this polymerized antitumor agent may be detected by a light scattering analysis using laser light or the like, and the physical properties of the associative aggregates may be measured by means of the value of scattered light intensity. That is, the physical properties of the associative aggregates may be defined by taking the scattered light intensity as a measured value.
A polymerized antitumor agent having such associative properties behaves as nanoparticles that are produced in the body based on associative properties, and thereby exhibits pharmacokinetics such as described above. Thus, the polymerized antitumor agent is distributed at a high concentration in a tumor tissue, and releases an antitumor agent, thereby exhibiting a high antitumor effect. Therefore, for these polymerized antitumor agents, the associative properties of forming nanoparticles constitute an important factor for performance demonstration.
A drug-polymer conjugate pharmaceutical product such as described above is a pharmaceutical product that promotes high pharmacological activity and reduction of side effects by means of the pharmacokinetics based on the molecular weight of the polymer carrier and by slowly releasing the drug bonded thereto in an activated form. Therefore, such a drug-polymer conjugate pharmaceutical product needs to be produced into a preparation which undergoes less change in the molecular weight of the polymer carrier in a state of being stored as a preparation, that is, a preparation having excellent storage stability with suppressed molecular weight reduction.
As a preparation provided with storage stability for a drug-polymer conjugate pharmaceutical product taken into consideration, for example, Patent Literatures 5 and 6 disclose that change in the molecular weight of the polymer carrier and liberation of the camptothecin derivative are suppressed by producing a conjugate of a polysaccharide having carboxyl groups and a camptothecin derivative into a pharmaceutical preparation including a sugar or a sugar alcohol and a pH adjusting agent.
However, in the drug-polymer conjugate pharmaceutical products described in Patent Literatures 5 and 6, it is speculated that the drug-polymer conjugate pharmaceutical products do not form strong associates in the form of nanoparticles. Thus, the molecular weight of the polymer carrier is considered to function as a performance demonstrating factor. For this reason, molecular weight reduction by a chemical decomposition reaction caused by cleavage of chemical bonds of the carrier is a problem to be solved, and this suppression is the purpose of the invention. However, in regard to a polymerized antitumor agent based on a block copolymer, which employs polymerization by producing nanoparticles from associative aggregates as a performance managing factor, a stable pharmaceutical preparation for which it is intended to control the nanoparticle-forming ability is not known.